Therapeutic composition of sulfonamides



Patented Dec. 20, 1 949 SUIIFON $491,489" 'rritiitisr'liii'rljo, disappearance mirrors Clair E. Folsome, Plainfield; N.--J assign): o

orthc-zlharmaceutical Corporatiom-a (BOP-POI! tion of New Jersey This mv''fititri r matter and more culai lythos finding application in the therafieu sac. lri'it'sini'ore Sp cific aspects, the inven is" directed tor'iovel compositions especial l as genetic products which may be applied topically.

It has been that of) abndrifiai bacterial flora in they na' Oran" eant netner pmvidesa hazardi'n -f orf ahinfecti'on of'the Iifi 'gor wail or th era which? infection might pl'bgrfis'tb suh' 9i tag to become a general @riim ultimatelyreach such a conditidiijs to"ci-iisdatii"frorn a septicemia;

'(b) abnormal bacterial flora in the vaginapam tic pi ducts of protein-niteibol isfri are highly obffe cti'on'abl'- becau's t ee'nd' products have a. racter isticaily disagreeable odor and produce an objectionable condition cannethe' healing p'rii saute-i5; ancconizatienas wenas following majorcervicalsurgery, such as hysterectomy; (c) at normal bacterial flora in the vagina sometimes interferes with thenormal healing process following minor caviar surgery; such cautery or the table enpa'ge 2906 ofqou'rnal of American Chemicalpciety volume #1 2 29QQ-29if7 De= cember 1941, in the'article'by Bell and Roblin, the pKa value of sulfanilamide is 10.43. Philip B. Cowles in the Yale Journal of Biology and Medicine, volume 14, pages 599-604, July 1942, has established that in general the bacteriostatic power of a sulfonamide is at its maximum when its pKa approximates the pH of the culture medium and decreases progressively as the pH of the medium departs in either direction from that pH.

In the course of my experimentations with the various sulfonamides, I have discovered that an effective medium for controlling the aforesaid abnormal bacteria flora could be provided. For this purpose, I have provided a plurality of sulfonamides whose pKa values differ at least by 1 and for example are between 6 and 8 and 4 and 6, and preferably three of them, one having a pKa. between 6 and 8, one having a pKa between 5 and 6 and another having a pKa between 4 and 5. Of the number of sulfonamides available, I preiil'arly the anae peiestreptc'cocci w'hcse end 5s following ri iinor ervical surgery; such-as;

1 claim. (on. ti -5115') 2 fer the combination'efsulfathiazole; N acetylsulfan il ar-nideand N benzoylsulfanilamide. Byemploying these particularsulfonarnides in combination, I i have provided a medicament whose bacterfostaticactivity is atleast 80% of" maximum activity of the iridivdualsulfonarndes-over a pH- range of 3.5 to 8 whch is the pI-Iof the culture medium wanna-ravages dep'ridi'iigon the conditien of-the vaginaat any particular timer This combination is particularly efiectve bec'ause'during the reparative process of healing ina wag-ma a pH- of about 8,- there is a regression of i the pH to a value of 3.5 to 4. And, these particular suifonamides hac'teri'os t'atic action at pKas of approximately 7, 5.5 and 4 5 respeca tively. Sulfathiazole shows at least 89%of maxi inum bacteriostatic activityisthe pH range of 6110 8, N acetylsulfanilamide in the pH range of as to 6.5 and N} benzoylsulfanilamide in thepH range of 3.5 to 5.5. In addition, I have discovered that by usirig this particular combination; there is less cumulative absorption and more pro= no'un'c'ed local tissue-action than with sulfathiae zole alone inthe saine'concentratiom While the ratio of thes'e'isulionainiides may'vary; I'prefe-r that they be present in'a mixture in which the molar ratio ofthse threieomponents is approximately l te 1-t0' 1 They are preferably in such com'minuted;form that the particlesizeithereof is no greater than 4 microns?- For mgr-purposes theparticle size of said stufonamidesrmaybein the-range of 0.1to 41-111 ero'n'ssoas to eliminate irritation of wound surfaces with consequent retardation of-wourid he'al ing and the production of local area of chemical irritation producingscar tissue if large particles 'oi crystals o f-the sulfonamidee were employed.

While-sa id plurality of shonamides may be employed-without any further additions, it is'pref erable-to-combine therewith urea peroxide which serves to reduce the s'iilfoii-ah ii'de inhibiting activi- .ity ofisuch compounds as p-amino -benzoic acid and methionine normally present in body fluids and exudates at wound surfaces, and also because urea reduces the tendency of sulfonamides to injure the kidneys by preventing crystal growth. Urea peroxide in said combination has the added function of acting as a bactericidal agent complementing the sulfonamides in their therapeutic action. A still further function of the urea peroxide is that it sterilizes the finished product as it leaves the manufacturing assembly.

For my purposes, I prefer to employ a combination of a plurality of sulfonamides whose pKa values are in the range of 3.5 to 8 and whose combined bacteriostatic action over the entire pH range of 4 to 7.5 is at least about of the maximum bacteriostatic action of an individual sulfonamide at the most favorable pH therefor. This combination is preferably free of any su1 3 fonamide whose pKa is outside of the range of 2.5 to 9.

While the various combinations of this invention may be applied in the form of dry powder or in solution, I prefer to incorporate them in a water soluble or dispersible vehicle in which the active ingredients are readily and easily available. The vehicle should preferably possess a degree of tackiness thereby making it an aesthetically acceptable preparation which will not leak out of the vagina, making it unnecessary for the patient to use a sanitary napkin for more than minimal period during which lymph and other fluids might be escaping from the wound surfaces.

Into the oil in Water vehicle may be uniformly distributed a plurality of sulfonamides and preferably the three component sulfonamide combination without, but preferably with, said urea peroxide. The ratio by weight of said three component sulfonamide combination to said vehicle may be in the range of about 3 to 100 and 12 to 100. The ratio by weight of the urea peroxide to the combined weights of the sulfonamides may be in the range of about 1 to and 1 to 2.

The following is a specific and preferred example illustrating the active components and ratio of active components in an oil in water base, all parts given by weight.

Example III Sulfathiazole 3.4 N acetylsulfanilamide 2.88 N benzoylsulfanilamide 3.7 Urea peroxide 1 Base (oil in water dispersion) 89.04

Clinical experience with compositions embodying the present invention has shown that by employing them as topical vaginal medicaments the post-operative and post-conization leucorrheas may be reduced by nearly two-thirds and in addition mucosal healing and the reversion to the four normal physiological balances may be accomplished within a period of 12 to 21 days in contrast to the usual 42 to 56 days.

The compositions of the present invention are particularly useful in those vaginal conditions caused by the overgrowth of secondary bacterial invaders in the presence of broken down tissue. They have been found to be especially efiicacious in the following vaginitides:

. Post-operative vaginitis or cervicitis. Post-cauterization of cervix.

. Chronic adhesive vaginitis.

. Ulcerative vaginitides.

Post-radiation vaginitis and cervicitis. Post-conization cervicitis.

. Antepartum vaginitis and cervicitis.

. Postpartum vaginitis and cervicitis.

Dosages of about five grams of the composition shown in Example III, twice daily during the more serious extent of the condition and reducing the dose to one half to one quarter after 4 to 6 days, have been particularly effective.

a I claim:

A multiple sulfonamide therapeutic composition, for topical application showing synergism due to the differences in pKa values of the sulfonamides present, comprising substantially equimolar proportions of two and only two members of the group consisting of N -acetylsulfanilamide, N -benzoylsulfanilamide, and sulfathiazole.

CLAIR E. FOLSOME.

REFERENCES CITED The following references are of record in the file of this patent:

Yale J. Biol. and Med., July 1942, pages 599-604.

Amer. J. Surgery, May 1942, page 369.

Quarterly J. Pharmacy and Pharmacology, April-June 1942, page 136.

Clinical Medicine, July 1944, page 20.

J. A. M. A., July 24, 1943, page 855.

U. S. Naval Medical Bulletin, July 1943, pages 1118 to 1122 Lehr: Proc. Soc. Exptl. Biol. and Med., Jan. 1945, pages 1l14.

British Med. J., Aug. 16,1941, page 221.

J. Amer. Med. Assoc., May 23, 1942, pages 324-327; ibid., July 25, 1942, page 1055.

Certificate of Correction Patent N 0. 2,491,489 December 20, 1949 CLAIR E. FOLSOME It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows:

Column 1, lines 40 and 41, for December 1941 read December 1942; column 2, line 6, for indivdual read individual; iine 17, for the words activity is read activity in; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Oifice.

Signed and sealed this 18th day of April, A. D. 1950.

THOMAS F. MURPHY,

Assistant Gommim'oner of Patents. 

